The clinical objective in treatment of peptic ulcer disease is to decrease gastric acid secretion, based on the principle "no acid, no ulcer." Traditional peptic ulcer disease therapy involves control of diet and the use of antacids and anticholinergics.
There is evidence indicating that histamine may be the final common pathway for stimulation of gastric secretion. This effect of histamine is mediated via H.sub.2 -reeceptors and is not inhibited by the classical antihistamines, which are H.sub.1 -receptor blockers. A number of specific H.sub.2 -receptor blocking agents (H.sub.2 -receptor antagonists) are now known. These compounds inhibit basal acid secretion, as well as secretion by other known gastric acid stimulants, and are useful in the treatment of peptic ulcers.
Burimamide (IIa) was the first clinically effective H.sub.2 -receptor antagonist. It inhibits gastric secretion in animals and man, but oral absorption is poor. ##STR2## Metiamide (IIb), a subsequently evaluated H.sub.2 antagonist, is more potent than burimamide and is orally active in man. Clinical utility was limited, however, owing to toxicity (agranulocytosis). Cimetidine (IIc) is as effective an H.sub.2 antagonist as metiamide, without producing agranulocytosis, and has recently been marketed as an anti-ulcer drug. The half-life of cimetidine is relatively short, thereby necessitating a therapeutic regimen of multi daily doses of 200-300 mg. tablets. There is thus a need for anti-ulcer agents which are longer acting and/or more potent than cimetidine.
Reviews on the development of H.sub.2 antagonists, including those discussed in the preceding paragraph, may be found in C. R. Ganellin, et. al., Federation Proceedings, 35, 1924 (1976), in Drugs of the Future, 1, 13 (1976), and in references cited therein. Relevant patents are as follows:
Belgian Pat. No. 841,814 (Farmdoc 90568X) discloses inhibitors of histamine-stimulated gastric secretion having the formula ##STR3## in which HET is one of eight named heterocyclic rings (including thiazole) which may be substituted by (lower)alkyl, hydroxyl, amino or halogen; Z is sulfur or CH.sub.2 ; X is S, CHNO.sub.2, NCN or NH; Y is NH.sub.2, (lower)alkylamino, di(lower)alkylamino, (lower)alkoxy, phenylethyl, imidazolylethyl, allyl, trifloroethyl or (CH.sub.2).sub.n R; n is 1-12; and R is OH, (lower)alkoxy, NH.sub.2 or (lower)alkylamino; provided that, when X is NH, Y is trifloroethyl or (CH.sub.2).sub.n R; and when X is NCN, Y may not be amino or (lower)alkylamino.
Belgian Pat. No. 804,144 (Farmdoc 19437V) discloses inhibitors of histamine-stimulated gastric acid secretion having the formula ##STR4## in which HET is a 5 or 6 membered heterocyclic ring containing nitrogen (thiazole is named), which may be substituted by alkyl, halogen, CF.sub.3, OH or NH.sub.2 ; m and n are each 0-4 and the sum of m and n is from 2 to 4; Z is sulfur, oxygen, NH or CH.sub.2 ; and R.sub.1 is hydrogen or (lower)alkyl.
U.K. Pat. No. 1,421,792 discloses H.sub.2 -receptor inhibitors of the formula ##STR5## wherein X and Y, which may be the same or different, are hydrogen, nitro, cyano or SO.sub.2 Ar, but may not both be hydrogen; R is hydrogen, (lower)alkyl or Het(CH.sub.2).sub.m Z(CH.sub.2).sub.n ; Z is sulfur or methylene; m is 0, 1 or 2 and n is 2 or 3 provided that the sum of m and n is 3 or 4; Het is an imidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole, triazole or thiadiazole ring which is optionally substituted by (lower)alkyl, hydroxy, halogen or amino; and Ar is phenyl, optionally substituted by halogen, methyl or amino.
U.S. Pat. No. 4,072,748 discloses histamine H.sub.2 -receptor inhibitors of the formula ##STR6## wherein Het is a nitrogen containing 5 or 6 membered heterocyclic ring (thiazole is one of 12 named heterocyclic rings) optionally substituted by (lower)alkyl, trifluoromethyl, hydroxyl, halogen or amino; Z is sulfur, oxygen, NH or a methylene group; m is 0, 1 or 2 and n is 2 or 3, the sum of m and n being from 2 to 4; X is COR.sub.3 ; CSR.sub.3, SO.sub.2 R.sub.4, NCHR.sub.5 or, when Z is methylene, may be nitro; R.sub.3 is (lower)alkyl, (lower)alkoxy or amino; R.sub.4 is (lower)alkyl, trifluoromethyl, amino or substituted or unsubstituted aryl, such as phenyl optionally substituted by halogen, (lower)alkyl or amino; R.sub.5 is substituted or unsubstituted aryl, such as phenyl; and R.sub.1 is hydrogen or (lower)alkyl such as methyl; and pharmaceutically acceptable salts thereof.
U.S. Pat. No. 4,022,797 discloses histamine H.sub.2 -receptor inhibitors of the formula ##STR7## wherein A, taken together with the carbon atom, forms an imidazole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole, isothiazole, oxazole, isoxazole, triazole, thiadiazole, benzimidazole or 5,6,7,8-tetrahydro[1,5-a]-pyridine ring; X.sub.1 is hydrogen, (lower)alkyl, hydroxyl, trifluoromethyl, benzyl, halogen, amino or ##STR8## X.sub.2 is hydrogen or, when X.sub.1 is (lower)alkyl, may be (lower)alkyl or halogen; k is 0 to 2 and m is 2 to 3, provided that the sum of k and m is 3 or 4; Y is oxygen, sulfur or NH; E is NR.sub.2 ; R.sub.1 is hydrogen, (lower)alkyl or di(lower)alkylamino(lower)alkyl; and R.sub.2 is hydrogen, nitro or cyano; and pharmaceutically acceptable addition salts thereof.
South African Pat. No. 78/2129 discloses histamine H.sub.2 -receptor antagonists of the formula ##STR9## in which X is sulfur or NH; Y is oxygen, sulfur, a direct bond, methylene, sulfinyl or a cis or trans vinylene radical; m is 0 to 4 and n is 1 to 4, provided that, when Y is sulfur, oxygen or sulfinyl, m is 1 to 4, and when Y is oxygen or sulfinyl, n is 2 to 4; R.sup.1 is hydrogen, halogen or (lower)alkyl; R.sup.2 is hydrogen, (lower)alkyl, (lower)alkanoyl or an aroyl group of from 7 to 11 carbon atoms; A is 3,4-dioxocyclobuten-1,2-diyl or a group of the formula C=Z in which Z is oxygen, sulfur, NCN, NNO.sub.2, CHNO.sub.2, NCONH.sub.2, C(CN).sub.2, NCOR.sup.3, NCO.sub.2 R.sup.3, NSO.sub.2 R.sup.3 or NR.sup.4 in which R.sup.3 is (lower)alkyl or an aryl group of from 6 to 12 carbon atoms, and R.sup.4 is hydrogen or (lower)alkyl; B is (lower)alkoxy, (lower)alkylthio or NR.sup.5 R.sup.6 in which R.sup.5 and R.sup.6 each are independently hydrogen, alkyl of from 1 to 10 carbon atoms, alkenyl of from 3 to 10 carbon atoms in which the double bond is seperated from the nitrogen atom by at least one carbon atom, cycloalkyl of from 3 to 8 carbon atoms, (primary hydroxy)alkyl of from 2 to 6 carbon atoms in which the oxygen atom is seperated from the nitrogen atom by at least two carbon atoms, alkoxyalkyl radicals of from 3 to 10 carbon atoms in which the oxygen atom is seperated from the nitrogen atom by at least two carbon atoms, alkylaminoalkyl of from 3 to 10 carbon atoms in which the nitrogen atom is separated from the nitrogen atom of NR.sup.5 R.sup.6 by at least two carbon atoms, or dialkylaminoalkyl of from 4 to 10 carbon atoms in which the nitrogen atom is separated from the nitrogen atom of NR.sup.5 R.sup.6 by at least two carbon atoms; and the pharmaceutically acceptable acid-addition salts thereof.
U.S. Pat. No. 4,112,234 discloses histamine H.sub.2 -receptor inhibitors of the formula ##STR10## wherein R.sup.1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, and processes for the preparation thereof.
This application relates to histamine H.sub.2 -receptor antagonists which are effective inhibitors of gastric secretion in animals, including man, which are useful in the treatment of peptic ulcer disease and which have the formula ##STR11## wherein R.sup.1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive; R.sup.2 and R.sup.3 each are independently hydrogen, (lower)alkyl, guanidino or --(CH.sub.2).sub.p NR.sup.4 R.sup.5 ; and R.sup.4 and R.sup.5 each are independently hydrogen, (lower)alkyl or phenyl; n is 2 or 3; p is 1, 2 or 3; X is NR.sup.6 or CHR.sup.6 ; R.sup.6 is cyano, nitro, SO.sub.2 Ar or SO.sub.2 (lower)alkyl; and Ar is phenyl or phenyl containing 1 or 2 substituents selected from halogen and (lower)alkyl; and nontoxic, pharmaceutically acceptable salts thereof.
A preferred embodiment of the invention is a compound of the formula ##STR12## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, or a nontoxic, pharmaceutically acceptable salt thereof.
Another preferred embodiment of the invention is a compound of the formula ##STR13## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, or a nontoxic, pharmaceutically acceptable salt thereof.
Another preferred embodiment of the invention is a compound of the formula ##STR14## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, or a nontoxic pharmaceutically acceptable salt thereof.
Another preferred embodiment of the invention is a compound of the formula ##STR15## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, and R.sup.8 and R.sup.9 each are independently hydrogen, halogen or (lower)alkyl, or a nontoxic, pharmaceutically acceptable salt thereof.
Another preferred embodiment of the invention is a compound of the formula ##STR16## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, and R.sup.8 and R.sup.9 each are independently hydrogen, halogen or (lower)alkyl, or a nontoxic, pharmaceutically acceptable salt thereof.
A more preferred embodiment of the invention is a compound of the formula ##STR17## wherein R.sup.1 and R.sup.2 are as defined above, or a nontoxic pharmaceutically salt thereof.
Another more preferred embodiment of the invention is a compound of the formula ##STR18## wherein R.sup.1 and R.sup.2 are as defined above, or a nontoxic, pharmaceutically acceptable salt thereof.
Another more preferred embodiment of the invention is a compound of the formula ##STR19## wherein m is an integer of from 1 to 6, inclusive; and R.sup.10 is hydrogen or methyl; or a nontoxic, pharmaceutically acceptable salt thereof.
Another more preferred embodiment of the invention is a compound of the formula ##STR20## wherein m is an integer of from 1 to 6, inclusive; and R.sup.10 is hydrogen or methyl; or a nontoxic, pharmaceutically acceptable salt thereof.
Another more preferred embodiment of the invention is a compound of the formula ##STR21## wherein R.sup.10 is hydrogen or methyl; or a nontoxic, pharmaceutically acceptable salt thereof.
Another more preferred embodiment of the invention is a compound of the formula ##STR22## wherein R.sup.10 is hydrogen or methyl, or a nontoxic, pharmaceutically acceptable salt thereof.
A most preferred embodiment of the invention is a compound of the formula ##STR23## or a nontoxic, pharmaceutically acceptable salt thereof.
Another most preferred embodiment of the invention is a compound of the formula ##STR24## or a nontoxic, pharmaceutically acceptable salt thereof.
Another most preferred embodiment of the invention is a compound of the formula ##STR25## or a nontoxic, pharmaceutically acceptable salt thereof.
Another most preferred embodiment of the invention is a compound of the formula ##STR26## or a nontoxic, pharmaceutically acceptable salt thereof.
Although the compounds of this invention have been shown as having the structure of Formula I, it will be appreciated by those skilled in the art that the compounds in which X is CHR.sup.6 can exist is various tautomeric forms, as follows: ##STR27## Also, the compounds in which X is CHR.sup.6 may exist as two geometric isomers, i.e., cis/trans isomers about the double bond. In addition, all the compounds of Formula I which contain a branched chain alkynyl group as substituent R.sup.1 may exist as their d- or 1-optical isomers as well as their racemic forms. Thus, for example, 3-amino-1-butyne of the formula ##STR28## may be resolved into its d- and l- isomers as described by A. Marszak-Fleury, Compt. rend., 242, 1046 (1956). The use of the d- or l- isomer of the alkynylamine in the preparation of a compound of Formula I produces the corresponding d- or l- isomer of the compound of Formula I. The present invention includes within its scope all possible tautomeric forms, geometric isomers and optical isomers of the compounds of Formula I as well as mixtures thereof.
The compounds of the present invention may be prepared by various alternative reaction schemes, as illustrated below for the two most preferred embodiments, compounds Im and In. ##STR29##
The reaction of compounds III and IV to produce compound V is described in U.S. Pat. No. 4,046,907. Analogous and homologous compounds are prepared by starting with the appropriate analog or homolog of compound III, which may be prepared by known procedures. The compound of formula IV is prepared by procedures described in Chem. Ber., 100, 591 (1967) or Acta Chem. Scand., 21, 2797 (1967). The reaction steps of Scheme I are conducted in a nonreactive solvent such as isopropyl alcohol at or above room temperature. The alkynylamines utilized as starting materials (propargylamine illustrated above) are either commercially available or may be prepared by procedures described in Bull. Soc. Chim. Fr., 490 (1958), Bull. Soc. Chim. Fr., 588 (1967), Bull. Soc. Chim. Fr., 592 (1967), Annales de Chimie (Paris), 3, 656 (1958) and J. Org. Chem., 21, 791 (1956). ##STR30##
The reaction is conducted in a non-reactive solvent such as methanol at or above room temperature. As will be appreciated by those skilled in the art, R.sup.11 may be any substituent such that --SR.sup.11 will be a suitable leaving group. Such leaving groups are conventional in the art. Thus, R.sup.11 may be (lower)alkyl, aryl or substituted aryl (e.g. p-nitrophenyl), or the like. The compounds of Formula VI may themselves be prepared by alternative procedures, such as illustrated below for the preparation of Compound VI wherein R.sup.11 is methyl. ##STR31##
The compound of Formula VII is prepared by the procedures described in Belgian Pat. No. 841,526 and analogous compounds may be prepared by analogous procedures. It will be apparent to those skilled in the art that, if the propargylamine utilized above is replaced by a different alkynylamine, there will be produced a compound of Formula VI which contains the different alkynyl group. That compound, in turn, can be reacted with a compound of Formula III to produce a compound of Formula I containing the different alkynyl group. ##STR32##
The reaction steps are conducted in a non-reactive solvent at or above room temperature. Compound VI is prepared as described above in Scheme II. Substituent Z in Compound IX is a conventional leaving group. Suitable leaving groups "Z" for use in this reaction are well-known to those skilled in the art. They include, for example, fluoro, chloro, bromo, iodo, --O.sub.3 SR.sup.12 wherein R.sup.12 is (lower)alkyl [e.g. methanesulfonate], --O.sub.3 SR.sup.13 wherein R.sup.13 is aryl or substituted aryl [e.g. benzenesulfonate, p-bromobenzenesulfonate or p-toluenesulfonate], --O.sub.3 SF, acetoxy and 2,4-dinitrophenoxy. For convenience and economy we normally prefer to utilize compound IX in which Z is chloro. The compound of Formula IX, and analogous compounds, are either commercially available or may be prepared by general procedures described in Zh. Obshch. Khim., 31, 1356 (1961) [C.A., 55, 24719f (1961)] and the references cited in Example 15, below. ##STR33##
The reaction is conducted in a non-reactive solvent at or above room temperature. The compound of Formula X, in which R.sup.11 is as described above, is prepared by oxidation of a compound of Formula VI by conventional means. ##STR34##
The reaction is conducted in a non-reactive solvent or at above room temperature. The compounds of Formula XI may be prepared by procedures described in our colleagues U.S. patent application Ser. No. 936,668, filed Aug. 24, 1978, the complete disclosure of which is incorporated herein by reference. For example, Compound XI in which R.sup.11 is methyl may be prepared by reacting dimethyl cyanodithioimidocarbonate with propargylamine. The dimethyl cyanodithioimidocarbonate may itself be prepared by procedures described in J. Org. Chem., 32, 1566 (1967). Analogous compounds may be prepared by analogous procedures. ##STR35##
The reaction, which is analogous to that described in Scheme III above, is conducted in a non-reactive solvent at or above room temperature. The compound of Formula XII and homologous and analogous compounds containing other alkynyl groups are described and claimed in our colleagues U.S. patent application Ser. No. 906,901, filed May 18, 1978, the complete disclosure of which is incorporated herein by reference. ##STR36##
The reaction, which is analogous to that described in Scheme IV above, is conducted in a non-reactive solvent at or above room temperature. The compounds of Formula XIII are prepared by oxidation of a compound of Formula XI by conventional means. ##STR37##
This reaction, which is analogous to that described in Scheme I above, is conducted in an inert solvent at or above room temperature. The compound of Formula XIV is prepared by the procedure described in J. Org. Chem., 32, 1566 (1967). The compound of Formula XV is itself disclosed in U.S. Pat. No. 3,950,333. Analogs and homologs of Compound XV are prepared by starting with the corresponding analogs or homologs of Compound III.
As used herein, the term nontoxic pharmaceutically acceptable salt means the mono- or di-salt of a compound of this invention with a nontoxic pharmaceutically acceptable organic or inorganic acid. Such acids are well known and include hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric, succinic, oxalic, benzoic, methanesulfonic, ethanedisulfonic, benzenesulfonic, acetic, propionic, tartaric, citric, camphorsulfonic, and the like. The salts are made by methods known in the art.
The term "(lower)alkyl," as used herein, means a straight or branched chain alkyl group containing from 1 to 6 carbon atoms. Similarly, the term "(lower)alkoxy" means an alkoxy group in which the alkyl portion is straight or branched and contains from 1 to 6 carbon atoms.
For therapeutic use, the pharmacologically active compounds of this invention will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in the basic form or in the form of a nontoxic pharmaceutically acceptable acid addition salt, in association with a pharmaceutically acceptable carrier.
The pharmaceutical compositions may be administered orally, parenterally or by rectal suppository. A wide variety of pharmaceutical forms may be employed. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile solution for injection, or an aqueous or non-aqueous liquid suspension. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation.
Preferably, each dosage unit will contain the active ingredient in an amount of from about 50 mg. to about 250 mg., and most preferably from about 100 mg. to about 200 mg. The active ingredient will preferably be administered in equal doses from two to four times a day. The daily dosage regimen will preferably be from 250 mg. to about 1000 mg., and most preferably from about 500 mg. to about 750 mg.
Histamine H.sub.2 -receptor antagonists have been shown to be effective inhibitors of gastric secretion in animals and man, Brimblecombe et al., J. Int. Med. Res., 3, 86 (1975). Clinical evaluation of the histamine H.sub.2 -receptor antagonist cimetidine has shown it to be an effective therapeutic agent in the treatment of peptic ulcer disease, Gray et al., Lancet, 1, 8001 (1977). The compounds prepared in Examples 1 (BL-6040) and 4 (BL-6044) have been compared with cimetidine in two standard tests. BL-6040 and BL-6044 have been found to be more potent than cimetidine as a histamine H.sub.2 -receptor antagonist in isolated guinea pig atria (in vitro) and more potent than cimetidine as an inhibitor of gastric acid secretion in rats (in vivo).